Inflammation is the most common feature of many chronic diseases and complications, while playing critical roles in carcinogenesis. Several studies have demonstrated that Nrf2 contributes to the anti-inflammatory process by orchestrating the recruitment of inflammatory cells and regulating gene expression through the antioxidant response element (ARE). The Keap1 (Kelch-like ECH-associated protein)/Nrf2 (NF-E2 p45-related factor 2)/ARE signaling pathway mainly regulates anti-inflammatory gene expression and inhibits the progression of inflammation. Therefore, the identification of new Nrf2-dependent anti-inflammatory phytochemicals has become a key point in drug discovery. In this review, we discuss the members of the Keap1/Nrf2/ARE signal pathway and its downstream genes, the effects of this pathway on animal models of inflammatory diseases, and crosstalk with the NF-κB pathway. In addition we also discuss about the regulation of NLRP3 inflammasome by Nrf2. Besides this, we summarize the current scenario of the development of anti-inflammatory phytochemicals and others that mediate the Nrf2/ARE signaling pathway.
Epidermal growth factor receptor mutations and susceptibility to targeted therapy in lung cancer AHMED SM, SALGIA R. Respirology 2006; 11: 687-692 Abstract: According to 2002 estimates, 1.35 million people were diagnosed with and 1.18 million died of lung cancer worldwide. Recently, a new class of medications targeting signal transduction pathways has come into focus in the treatment of various malignancies. In lung cancer, the molecules gefitinib and erlotinib which target the intracellular kinase domain of the epidermal growth factor receptor (EGFR), cause significant tumour responses and, in the case of erlotinib, a survival benefit in patients with previously treated cancers. Responses were most pronounced in female nonsmokers with adenocarcinoma histology. These patients were found more likely to harbour mutations of the receptor kinase domain, including in-frame deletions in exon 19 (such as deletions of codons 746-750) and point deletions in exon 21 (such as L858R). Other EGFR kinase domain mutations have been found to confer resistance (T790M) or differential susceptibility to erlotinib and gefitinib (E884K). Gene amplification of EGFR also may predict sensitivity, although the mechanism by which this occurs is unclear, because level of expression detected by immunohistochemistry has not been correlated with increased sensitivity. Phenotypic and genotypic epithelial to mesenchymal transition may be an indicator of resistance to EGFR kinase inhibitors. In this article, we review efforts that have been undertaken to identify genomic determinants of drug susceptibility to EGFR tyrosine kinase inhibitors, with particular focus on the role of gene mutations.
Effective methods for predicting tumor response to preoperative chemotherapy are required. Aldo-ketoreductase family 1 member B10 (AKR1B10) is predominantly expressed in the gastrointestinal tract and serves an important function in cancer development and progression. The present study investigated whether AKR1B10 expression may predict the therapeutic response of locally advanced gastric cancer. A total of 53 patients with gastric cancer underwent neoadjuvant chemotherapy followed by surgery between January 2006 and December 2015. The protein expression level of AKR1B10 was determined in paraffin-embedded biopsy specimens using immunohistochemistry. Western blotting confirmed that the AKR1B10 protein is primarily localized to the cytoplasm. χ2 and Fisher's exact tests were used to determine the association of AKR1B10 with a number of clinic opathological features. Univariate and multivariate analyses were used to identify the prognostic factors. Survival rates were compared using Kaplan-Meier curves with a log-rank test. The positive rate of AKR1B10 protein expression was 58.5%, whereas 41.5% samples exhibited negative expression. The frequency of AKR1B10-positive gastric cancer samples was increased in patients with lymph node metastasis and decreased in those exhibiting tumor regression. The 5-years overall survival rate for the AKR1B10-positive group was significantly poorer than that for the AKR1B10-negative group. AKR1B10 expression was associated with lymph node metastasis and a poorer prognosis, along with a poor response to neoadjuvant chemotherapy suggesting that AKR1B10 may be a potential predictor for the therapeutic response of locally-advanced gastric cancer.
Abstract. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a variety of tumor cells by engaging the death receptors 4 (DR4) and 5 (DR5). We investigated the effect of chemotherapeutic drugs on DR4-mediated apoptosis in human bladder cancer cells, using a human monoclonal agonistic antibody specific for DR4, mapatumumab. Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Synergy was assessed by isobolographic analysis. Treatment of human bladder cancer T24 cells with mapatumumab in combination with mitomycin C, vinblastine or gemcitabine did not overcome resistance to these agents. However, treatment with mapatumumab in combination with epirubicin (EPI) had a synergistic cytotoxic effect. Synergy was also obtained in KU7 and RT112 human bladder cancer cells. A synergistic effect was also observed with mapatumumab in combination with pirarubicin. The synergy obtained in cytotoxicity with mapatumumab and EPI was also achieved in apoptosis. EPI markedly increased DR4 expression in the bladder cancer cells at both the mRNA and protein levels. Furthermore, the combination-induced cytotoxicity was significantly suppressed by the DR4:Fc chimeric protein. The combination of EPI and mapatumumab significantly activated the caspase cascade, including caspase-8, -9 and -3, which are the downstream molecules of death receptors. These findings indicate that EPI sensitizes bladder cancer cells to DR4-mediated apoptosis through induction of DR4 and activation of caspases, suggesting that the combination therapy of EPI and mapatumumab may be effective for bladder cancer therapy. IntroductionEach year more than 350,000 new cases of bladder cancer are diagnosed globally (1), making bladder cancer the ninth most frequent cancer worldwide (2). Epirubicin (EPI) and pirarubicin (THP) are a new generation of anthracycline drugs, widely used as anticancer chemotherapeutic agents in various types of cancers including bladder cancer (2,3). Furthermore, these anthracycline drugs are less cardiotoxic than doxorubicin. However intrinsic and acquired resistance to chemotherapeutic drugs are considered as major problems. Therefore, it is important to develop new treatment strategies for bladder cancer patients to prevent recurrence and reduce the risk of tumor progression.Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic member of the TNF superfamily and a potentially effective anticancer agent. TRAIL has been identified as a powerful activator of programmed cell death or apoptosis in various tumor cells, yet is considered relatively nontoxic against most normal cells (4-6). TRAIL induces apoptosis by interacting with two death-inducing receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) following activation of the caspase cascade that initiates both extrinsic and intrinsic apoptotic pathways (4,7-9). In addition, TRAIL binds to two other receptors, TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2), which lack a functional cytoplasmic death dom...
Approximately 475,000 cases of squamous cell carcinoma (SCCHN) of the head and neck occur worldwide. Whereas significant advances have been made in the treatment of early and locally advanced disease, the prognosis for recurrent and metastatic (R/M) disease remains poor. Compounds with demonstrated activity include cisplatin and carboplatin, antimicrotubular compounds such as taxanes and vinorelbine, and fluoropyrimidines. In refractory and metastatic disease, regimens combining platinum agents with taxanes or fluorouracil based agents produce a 30% response rate and a median overall survival of six to eight months. Newer three agent chemotherapy regimens have produced response rates in the range of 40-50%, without significant improvements in overall survival noted. Recently, a new class of medications targeting signal transduction pathways has come into focus in the treatment of various malignancies. In SCCHN, given the high prevalence of expression of the epidermal growth factor receptor (EGFR) and its role in promoting cellular growth and proliferation, molecules targeting the receptor's intracellular kinase domain are a logical strategy. The agents gefitinib and erlotinib have yielded response rates in the 5-15% range when used as single agents. In addition, newer agents with broad activity against the EGFR and other related erbB receptor family members are being developed in clinical trials. Strategies to enhance the activity of EGFR tyrosine kinase inhibitors (TKIs) in treating SCCHN are being investigated, as well as strategies to select individuals with tumors more likely to respond to these drugs. This article reviews the advances that have made in treating refractory and metastatic disease, with particular focus on the challenges that are faced in successfully translating EGFR inhibition as a paradigm of tumor treatment in SCCHN.
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